CN107445935A - A kind of hesperetin analog derivative of amide groups substitution and its preparation and as the application in the medicine of anti-inflammatory - Google Patents
A kind of hesperetin analog derivative of amide groups substitution and its preparation and as the application in the medicine of anti-inflammatory Download PDFInfo
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Abstract
The invention belongs to pharmaceutical chemistry and pharmacotherapeutics field, hesperetin analog derivative and its preparation and as the application in the medicine of anti-inflammatory of a kind of amide groups substitution are disclosed.Research has shown that the hesperetin analog derivative of amide groups involved in the present invention substitution can suppress NO release, reduces inflammatory mediator IL 6 and TNF α generation, while also obvious suppression nitricoxide synthase（iNOS）With COX 2 expression.Therefore show that such compound can develop into the medicine of anti-inflammatory.
Description
Technical field
The invention belongs to pharmaceutical chemistry and pharmacotherapeutics field, and in particular to a kind of hesperetin class of amide groups substitution is spread out
Biology and its as the application in the medicine for preparing anti-hepatic fibrosis.
Background technology
Inflammation is all the big killer in human and animal's life since ancient times, and its definition is：With vascular system
Biological tissue to continuous developments of a kind of defense reaction Jing Guo medical technology caused by local damage caused by a variety of causes and
The continuous research of people, have found finally some can resist inflammation torment medicine, but these medicines in clinical medicine
On should be far from being enough.Nineteen twenty-nine, the prosperous neat research at first of American pathologists find steroidal anti-inflammatory drugs " cortisone ", and this is
A big important breakthrough of the mankind in anti-inflammatory agent field.But taking for anti-inflammatory agent can be had for a long time with certain side effect and time
Tolerance.For example the incidence, aspirin etc. of COX-2 selective depressants increase miocardial infarction and apoplexy has necessarily to stomach
The injury of degree.These side effects are overcome to become an important problem of research anti-inflammatory agent, so the development of anti-inflammatory agent is ground
Study carefully the focus that never stopping and field of medicaments are attracted attention.
Inflammation is the complicated defense reaction that there is the living organism of vascular system damage factor to be occurred.When body by
When being invaded to inflammatory factor, body eliminates pro-inflammatory cytokine self by inflammatory reaction, and this is the process of a damage and antibody Monoclonal.
Many common diseases (such as autoimmune disease, atherosclerosis, wound repair) belong to inflammation category.It is every can
The medicine to diminish inflammation is referred to as anti-inflammatory drug, and it can suppress or block the generation and release of inflammatory mediator, suppresses inflammatory
Reaction.In recent years, the continuous research recognized with people inflammation mechanism gos deep into and the extensive use of molecular biotechnology, anti-inflammatory
The research of medicine gradually develops into cell, molecular level from organ-tissue is horizontal, gradually prepares more multi items, scope
Wider array of medicine.
Inflammation is a complicated process by some proinflammatory cell factors and inflammatory molecule mediation.Such as research hair
Existing, vascular endothelial cell NO secretions increase after e. coli lipopolysaccharide stimulates, the new drug that the secretion currently for NO suppresses is ground
Study carefully and progressively deploy.When body is infected, peritoneal macrophage is stimulated by a large amount of lipopolysaccharides, produces substantial amounts of IL-1, IL-
6 and TNF-a, they are mutually induced, mutually collaboration.Due to being present in excess for these cell factors, arachidonic acid generation is accelerated
Thank, the inflammatory mediator such as release thromboxane A2, prostaglandin, leukotriene, cause excessive inflammatory response.In new drug design and researched and developed
Cheng Zhong, whether can suppress inflammatory factor NO, IL-6 and TNF-α according to pharmaceutical activity is released to basic, designs one
A little new compounds for being likely to become anti-inflammatory, then further according to its compound characteristic research it be likely to become the machine of anti-inflammatory agent
System, such as inflammation lead to NF-KB and MAPK paths, and these are all the main basic according to in medical research neighborhood of preliminary screening
Development provides immeasurable experiment basis.
The content of the invention
To achieve the above object, the present invention provide hesperetin analog derivative of a kind of amide groups substitution and preparation method thereof and
Using.
The present invention is achieved by the following technical solutions：
The hesperetin analog derivative of a kind of amide groups substitution, it is characterised in that structural formula is：
Wherein R1Represent to diethylin, n-propylamine base, n-butylamine-based, isobutyl amine, pyrrolidinyl, sugared amino, N- first
Base piperazinyl, NEP base, morpholine base, benzene ethylamino, adjacent chlorobenzene ethylamino, adjacent fluorobenzene ethylamino, a chlorobenzene second ammonia
Base, to bromobenzene ethylamino, to chlorobenzene ethylamino, to fluorophenethyl amido, to methoxybenzene ethylamino, benzyl amino, O-methoxy benzyl
Amido, meta-methoxy benzamido group, 4-Methoxybenzylamine base, adjacent fluorine benzyl amino, adjacent benzyl chloride amino, to benzyl chloride amino, to fluorine benzyl ammonia
Base, to bromobenzylamino, one kind in benzylamino.
The preparation method of the hesperetin analog derivative of described amide groups substitution, it is characterised in that：
Preparation method comprises the following steps：
(1) by hesperetinStirred with the 3-5 times of ethyl crotonate measured under weak base effect
Product is obtained after mixing
(2) after step (1) products therefrom being hydrolyzed into reaction, then mix with various amine, acid amides glycosylation reaction obtains end
The hesperetin analog derivative of product amide base substitutionWherein R1 is diethyl
Amido, n-propylamine base, n-butylamine-based, isobutyl amine, pyrrolidinyl, sugared amino, N methyl piperazine base, NEP base,
Coffee quinoline base, benzene ethylamino, adjacent chlorobenzene ethylamino, adjacent fluorobenzene ethylamino, a chlorobenzene ethylamino, to bromobenzene ethylamino, to chlorobenzene second
Amino, to fluorophenethyl amido, to methoxybenzene ethylamino, benzyl amino, O-methoxy benzamido group, meta-methoxy benzamido group, to first
Epoxide benzamido group, adjacent fluorine benzyl amino, adjacent benzyl chloride amino, to benzyl chloride amino, to fluorine benzyl amino, to bromobenzylamino, trifluoromethyl benzyl
One kind in amino.
The preparation method of the hesperetin analog derivative of described amide groups substitution, it is characterised in that：Weak base is in step (1)
K2CO3, stirring, mixing time is 6 hours, reaction dissolvent DMF.
The preparation method of the hesperetin analog derivative of described amide groups substitution, it is characterised in that hydrolysis exists in step (2)
Under alkalescence condition, catalyst is sodium hydroxide, and solvent is water and methanol；Amino substitutionization reaction temperature is room temperature, in HOBT and
Carried out under the catalysis of EDC hydrochlorides, solvent is chloroform.
The application of the hesperetin analog derivative of described amide groups substitution, it is characterised in that as preparing in anti-anti-inflammatory drug
Application.
Described application, described medicine are injection, tablet, pill, capsule, suspending agent or emulsion.
The preparation method of the hesperetin analog derivative of amide groups substitution of the present invention, principal synthetic routes are：
It is concretely comprised the following steps：
(1) by hesperetinMixed with the DMF solvent of 20 times of amounts, what 3-5 times of addition was measured
Ethyl crotonate, in K2CO3In the presence of stir 1 hour after, with ethyl acetate saturated aqueous common salt repeatedly extract remove DMF, do
Dry, revolving recovery ethyl acetate, solid with ethyl acetate methanol, petroleum ether re-crystallizing in ethyl acetate, obtains product successively
(2) above-mentioned product is dissolved in water and in methanol, reaction unit is put in condition of ice bath, added appropriate 10%NaOH and adjust
PH to 12 to 13 or so, 5h, terminating reaction are reacted, acid adding separates out, and suction filtration obtains hydrolysate, dries.Dissolved, then added with chloroform
The fatty amine of 5 times of amounts, appropriate HOBT and EDC hydrochlorides, stirring reaction are overnight.Stop reaction, dry, silica gel column chromatography, obtain
To the hesperetin derivant of final product amide groups substitutionR1 is diethyl
Amido, n-propylamine base, n-butylamine-based, isobutyl amine, pyrrolidinyl, sugared amino, N methyl piperazine base, NEP base,
Coffee quinoline base, benzene ethylamino, adjacent chlorobenzene ethylamino, adjacent fluorobenzene ethylamino, a chlorobenzene ethylamino, to bromobenzene ethylamino, to chlorobenzene second
Amino, to fluorophenethyl amido, to methoxybenzene ethylamino, benzyl amino, O-methoxy benzamido group, meta-methoxy benzamido group, to first
Epoxide benzamido group, adjacent fluorine benzyl amino, adjacent benzyl chloride amino, to benzyl chloride amino, to fluorine benzyl amino, to bromobenzylamino, trifluoromethyl benzyl
One kind in amino.
Beneficial effect：
The hesperetin analog derivative of amide groups substitution involved in the present invention can suppress NO release, reduce inflammatory mediator
IL-6 and TNF-α generation, while also obvious suppression nitricoxide synthase (iNOS) and COX-2 expression.Therefore such is shown
Compound can develop into the medicine of anti-inflammatory.
Specific embodiment：
The present invention is further described with reference to specific embodiment.Unless stated otherwise, the present invention use reagent,
Apparatus and method are the art routinely reagent, equipment and conventional use of method purchased in market.
Embodiment one：The synthesis of compound 2
By compound 1, i.e. hesperetin(11.44g, about 0.04mol) is dissolved in 200mL
In dry DMF, the K of 2 times of moles is added2CO3, then add 3 to 5 times of ethyl crotonates measured, stirring at normal temperature 1h.Terminate anti-
Should, extracted repeatedly with ethyl acetate saturated aqueous common salt, remove DMF, obtain yellow semifinished product.By yellow semifinished product with a small amount of acetic acid
Ethyl ester is dissolved, and the methanol of 5 times of amounts is added under heated condition, stands cooling, separates out faint yellow solid, is filtered, and after drying, uses acetic acid
Ethyl ester petroleum ether recrystallizes, and stands cooling, there is white needle-like crystals precipitation, filters, and dries, obtains white crystal, i.e. compound 2
(9.62g), yield 68%.1H NMR(400MHz,DMSO)δ12.09(s,1H,5-OH),9.08(s,1H,3’-OH),6.99–
6.91 (m, 3H, C=OC=CH, 2 '-H, 4 '-H), the 6.88 (- H of dd, J=8.4,1.8Hz, 1H, 5 '), 6.16 (d, J=2.2Hz,
1H, 8-H), 6.14 (d, J=2.2Hz, 1H, 6-H), 6.07 (d, J=15.8Hz, 1H, C=OCH=C), 5.49 (dd, J=
12.5,2.9Hz, 1H, 2-H), 4.87 (dd, J=3.9,1.7Hz, 2H, C=CCH2), O 4.14 (q, J=7.1Hz, 2H, OCH2),
3.78(s,3H,OCH3), 3.27 (dd, J=17.2,12.6Hz, 1H, 3-H), 2.75 (dd, J=17.1,3.1Hz, 1H, 3-H),
1.21 (t, J=7.1Hz, 3H, OCCH3).13C NMR(101MHz,DMSO)δ196.86,165.70,165.08,163.14,
162.76,147.93,146.46,142.72,130.91,121.19,117.70,114.09,111.96,102.89,95.20,
94.34,78.44,66.47,60.14,55.65,42.11,14.04.TOF-HRMS:m/z[M+H]+calcd for C22H23O8:
415.1396；found:415.1396.
The chemical formula of compound 2 is as follows：
Embodiment two：The synthesis of compound 3
Compound 2 (3.72g, 10mmol), is dissolved in methanol aqueous solution, ice bath, and 10%NaOH is added dropwise, and adjusts PH to 12 to 13
Left and right, 2h is reacted, add watery hydrochloric acid to adjust PH to 2 to 3 or so, terminating reaction, add elutriation to go out, filtered, obtain yellow semifinished product；It is rough
Product ethyl alcohol recrystallization, wait faint yellow solid, i.e. compound 3.1H NMR(400MHz,DMSO)δ12.48(s,1H,COOH),
12.09 (s, 1H, 5-OH), the 9.09 (- OH of s, 1H, 3 '), 6.96-6.84 (m, 4H, 2 '-H, 4 '-H, 5 '-H, C=OC=CH),
6.16 (d, J=2.3Hz, 1H, 8-H), 6.13 (d, J=2.3Hz, 1H, 6-H), 5.99 (dt, J=15.7,1.6Hz, 1H, C=
), OCH=C 5.49 (dd, J=12.5,2.9Hz, 1H, 2-H), 4.85 (dd, J=4.1,1.7Hz, 2H, C=CCH2O),3.78
(s,3H,OCH3), 3.27 (dd, J=17.2,12.5Hz, 1H, 3-H), 2.75 (dd, J=17.1,3.1Hz, 1H, 3-H)13C
NMR(101MHz,DMSO)δ196.85,166.49,165.76,163.14,162.76,147.92,146.46,141.94,
130.92,122.38,117.71,114.09,111.96,102.87,95.22,94.35,78.44,66.52,55.65,
42.11.TOF-HRMS:m/z[M+H]+calcd for C20H18O8:386.1074；found:386.1071.
The chemical formula of compound 3 is as follows：
Embodiment three：Compound 3a synthesis
Weigh and take compound 3 (0.39g, 1mmol), be dissolved in 30ml chloroforms, add the benzylamine of 3 times of amounts, add appropriate HOBT and EDC
Hydrochloride, it is stirred overnight at room temperature.Stop reaction, reaction solution is transferred in extraction flask, adjust PH to be washed to weak acid with saturated common salt
(40mL × 3) are washed, organic phase is dried with anhydrous calcium chloride, filtering, the light yellow oil of filtrate decompression distillation.Use silica gel column layer
Analysis purifying [V (chloroform)：V (petroleum ether)=3：1] white solid 3a is obtained.1H NMR(400MHz,CDCl3)δ11.98(s,
1H, 5-OH), 7.37-7.26 (m, 5H, Ar-H), the 7.03 (- H of d, J=2.0Hz, 1H, 2 '), 6.97 (dt, J=15.3,4.0Hz,
1H, C=OC=CH), the 6.92 (- H of dd, J=8.4,2.0Hz, 1H, 5 '), the 6.88 (- H of d, J=8.3Hz, 1H, 4 '), 6.10 (dt,
J=15.3,1.9Hz, 1H, C=OCH=C), 6.05 (d, J=2.3Hz, 1H, 8-H), 6.03 (d, J=2.3Hz, 1H, 6-H),
5.86 (t, J=5.3Hz, 1H, NH), 5.32 (dd, J=12.8,3.0Hz, 1H, 2-H), 4.70 (dd, J=3.9,2.0Hz, 2H,
C=CCH2), O 4.52 (d, J=5.7Hz, 2H, Ar-CH2N),3.91(s,3H,OCH3), 3.06 (dd, J=17.2,12.9Hz,
1H, 3-H), 2.78 (dd, J=17.2,3.1Hz, 1H, 3-H) .TOF-HRMS:m/z[M+H]+calcd for C27H26NO7:
476.1704；found:476.1710.
Compound 3a chemical formula is as follows：
Example IV：Compound 3b synthesis
Method is with embodiment two, except that replacing benzylamine with to chlorobenzylamine, obtains white solid 3b.1H NMR
(400MHz, DMSO) δ 12.09 (s, 1H, 5-OH), the 9.08 (- OH of s, 1H, 3 '), 8.64 (t, J=5.9Hz, 1H, NH), 7.37
(d, J=8.4Hz, 2H, Ar-H), 7.27 (d, J=8.4Hz, 2H, Ar-H), 6.94 (m, 2H, 2 '-H, 4 '-H), 6.88 (dd, J
=8.4,1.6Hz, 1H, 5 '-H), 6.75 (dt, J=15.6,4.3Hz, 1H, C=OC=CH), 6.20 (d, J=15.6Hz, 1H,
), C=OCHC=C 6.14 (d, J=2.1Hz, 1H, 8-H), 6.11 (d, J=2.1Hz, 1H, 6-H), 5.49 (dd, J=12.5,
2.8Hz, 1H, 2-H), 4.84 (d, J=2.7Hz, 2H, Ar-CH2), N 4.32 (d, J=5.9Hz, 2H, C=CCH2O),3.78(s,
3H,OCH3), 3.26 (dd, J=17.2,12.6Hz, 1H, 3-H), 2.75 (dd, J=17.1,3.0Hz, 1H, 3-H) .TOF-
HRMS:m/z[M+Na]+calcd for C27H24ClNNaO7:532.1134；found:532.1135.
Compound 3b chemical formula is as follows：
Embodiment five：Compound 3c synthesis
Method is with embodiment two, except that replacing benzylamine with 4-Fluorobenzylamine, obtains white solid 3c.1H NMR
(400MHz, DMSO) δ 12.09 (s, 1H, 5-OH), the 9.08 (- OH of s, 1H, 3 '), 8.61 (t, J=5.9Hz, 1H, NH), 7.31-
7.26(m,2H,Ar-H),7.18–7.10(m,2H,Ar-H),6.96–6.85(m,3H,2’-H,4’-H,5’-H),6.75(dt,J
=15.6,4.3Hz, 1H, C=OC=CH), 6.23-6.16 (dt, J=15.5,1.4Hz, C=OCH=C), 6.13 (d, J=
2.3Hz, 1H, 8-H), 6.11 (d, J=2.3Hz, 1H, 6-H), 5.49 (dd, J=12.4,2.9Hz, 1H, 2-H), 4.84 (dd, J
=4.1,1.5Hz, 2H, C=CCH2), O 4.31 (d, J=5.9Hz, 2H, Ar-CH2N),3.78(s,3H,OCH3),3.26(dd,J
=17.2,12.5Hz, 1H, 3-H), 2.75 (dd, J=17.2,3.1Hz, 1H, 3-H) .TOF-HRMS:m/z[M+Na]+calcd
for C27H24FNNaO7:516.1429；found:514.1429.
Compound 3c chemical formula is as follows：
Embodiment six：Compound 3d synthesis
Method is with embodiment two, except that replacing benzylamine with to bromobenzyl ammonia, obtains white solid 3d.1H NMR
(400MHz, DMSO) δ 12.09 (s, 1H, 5-OH), the 9.08 (- OH of s, 1H, 3 '), 8.64 (t, J=6.0Hz, 1H, NH), 7.53-
7.48 (m, 2H, Ar-H), 7.23-7.18 (m, 2H, Ar-H), 6.96-6.91 (m, 2H, 2 '-H, 4 '-H), 6.88 (dd, J=
8.4,2.0Hz, 1H, 5 '-H), 6.75 (dt, J=15.6,4.3Hz, 1H, C=OC=CH), 6.20 (dt, J=15.4,1.6Hz,
1H, C=OCH=C), 6.14 (d, J=2.3Hz, 1H, 8-H), 6.11 (d, J=2.3Hz, 1H, 6-H), 5.49 (dd, J=
12.5,3.0Hz, 1H, 2-H), 4.84 (dd, J=4.2,1.6Hz, 2H, C=CCH2), O 4.30 (d, J=5.9Hz, 2H, Ar-
CH2N),3.78(s,3H,OCH3), 3.26 (dd, J=17.2,12.5Hz, 1H, 3-H), 2.75 (dd, J=17.1,3.1Hz, 1H,
3-H).TOF-HRMS:m/z[M+H]+calcd for C27H24BrNNaO7:576.0630；found:576.0630.
Compound 3d chemical formula is as follows：
Embodiment seven：Compound 3e synthesis
Method is with embodiment two, except that replacing benzyl ammonia with 4-Methoxybenzylamine, obtains white solid 3e.1H NMR
(400MHz, DMSO) δ 12.08 (s, 1H, 5-OH), the 9.08 (- OH of s, 1H, 3 '), 8.52 (t, J=5.9Hz, 1H, NH), 7.20-
7.15(m,2H,Ar-H),6.97–6.91(m,2H,2’-H,4’-H),6.91–6.84(m,3H,Ar-H,5’-H),6.73(dt,J
=15.6,4.4Hz, 1H, C=OC=CH), 6.19 (d, J=15.6Hz, 1H, C=OCH=C), 6.13 (d, J=2.3Hz, 1H,
8-H), 6.10 (d, J=2.3Hz, 1H, 6-H), 5.48 (dd, J=12.5,3.0Hz, 1H, 2-H), 4.83 (dd, J=4.1,
1.4Hz, 2H, C=CCH2), O 4.25 (d, J=5.8Hz, 2H, Ar-CH2N),3.77(s,3H,OCH3),3.72(s,3H,
OCH3), 3.26 (dd, J=17.2,12.5Hz, 1H, 3-H), 2.74 (dd, J=17.1,3.1Hz, 1H, 3-H) .TOF-HRMS:
m/z[M+H]+calcd for C28H28NO8:506.1809；found:506.1813.
Compound 3e chemical formula is as follows：
Embodiment eight：Compound 3f synthesis
Method, except that replacing benzyl ammonia with 4- trifluoromethyl benzyl ammonia, obtains white solid 3f with embodiment two.1H NMR
(400MHz, DMSO) δ 12.09 (s, 1H, 5-OH), the 9.08 (- OH of s, 1H, 3 '), 8.72 (t, J=6.0Hz, 1H, NH), 7.69
(d, J=8.2Hz, 2H, Ar-H), 7.47 (d, J=8.1Hz, 2H, Ar-H), 6.96-6.91 (m, 2H, 2 '-H, 4 '-H), 6.88
(- the H of dd, J=8.3,1.9Hz, 1H, 5 '), 6.76 (dt, J=15.6,4.3Hz, 1H, C=OC=CH), 6.22 (d, J=
15.6Hz, 1H, C=OCH=C), 6.14 (d, J=2.2Hz, 1H, 8-H), 6.11 (d, J=2.2Hz, 1H, 6-H), 5.49 (dd,
J=12.5,2.9Hz, 1H, 2-H), 4.85 (d, J=2.7Hz, 2H, C=CCH2), O 4.42 (d, J=5.9Hz, 2H, Ar-
CH2N),3.78(s,3H,OCH3), 3.27 (dd, J=17.2,12.6Hz, 1H, 3-H), 2.75 (dd, J=17.2,3.1Hz, 1H,
3-H).TOF-HRMS:m/z[M+H]+calcd for C28H25F3NO7:544.1578；found:544.1580.
Compound 3f chemical formula is as follows：
Embodiment nine：Compound 3g synthesis
Method, except that replacing benzyl ammonia with adjacent benzyl chloride ammonia, obtains white solid 3g with embodiment two.1H NMR
(400MHz,CDCl3)δ11.99(s,1H,5-OH),7.44–7.34(m,2H,Ar-H),7.25–7.21(m,2H,Ar-H),
The 7.03 (- H of d, J=2.0Hz, 1H, 2 '), 6.96 (dt, J=15.7,4.1Hz, 1H, C=OC=CH), 6.92 (dd, J=8.4,
- the H of 2.1Hz, 1H, 5 '), the 6.88 (- H of d, J=8.3Hz, 1H, 4 '), 6.12 (dt, J=15.3,1.9Hz, 1H, C=OCH=C),
6.05 (d, J=2.3Hz, 1H, 8-H), 6.04 (d, J=2.3Hz, 1H, 6-H), 6.00 (t, J=5.9Hz, 1H, NH), 5.33
(dd, J=12.8,3.0Hz, 1H, 2-H), 4.69 (dd, J=3.9,2.0Hz, 2H, C=CCH2O), 4.61 (d, J=6.0Hz,
2H,Ar-CH2N),3.92(s,3H,OCH3), 3.07 (dd, J=17.2,12.9Hz, 1H, 3-H), 2.79 (dd, J=17.2,
3.1Hz,1H,3-H).TOF-HRMS:m/z[M+Na]+calcd for C27H24ClNNaO7:532.1134；found:
532.1137.
Compound 3g chemical formula is as follows：
Embodiment ten：Compound 3h synthesis
Method, except that replacing benzyl ammonia with adjacent fluorine benzyl ammonia, obtains white solid 3h with embodiment two.1H NMR
(400MHz, DMSO) δ 12.09 (s, 1H, 5-OH), the 9.08 (- OH of s, 1H, 3 '), 8.60 (t, J=5.8Hz, 1H, NH), 7.35-
(7.27 m, 2H, Ar-H), 7.20-7.13 (m, 2H, Ar-H), 6.96-6.91 (m, 2H, 2 '-H, 4 '-H), 6.88 (dd, J=
8.4,2.0Hz, 1H, 5 '-H), 6.74 (dt, J=15.6,4.3Hz, 1H, C=OC=CH), 6.21 (dt, J=15.4,1.6Hz,
1H, C=OCH=C), 6.13 (d, J=2.3Hz, 1H, 8-H), 6.11 (d, J=2.3Hz, 1H, 6-H), 5.49 (dd, J=
12.5,3.0Hz, 1H, 2-H), 4.84 (dd, J=4.2,1.6Hz, 2H, C=CCH2), O 4.37 (d, J=5.7Hz, 2H, Ar-
CH2N),3.78(s,3H,OCH3), 3.26 (dd, J=17.2,12.5Hz, 1H, 3-H), 2.75 (dd, J=17.2,3.1Hz, 1H,
3-H).TOF-HRMS:m/z[M+H]+calcd for C27H25FNO7:494.1610；found:494.1606.
Compound 3h chemical formula is as follows：
Embodiment 11：Compound 3i synthesis
Method, except that replacing benzyl ammonia with 2- methoxybenzyl ammonia, obtains white solid 3i with embodiment two.1H NMR
(400MHz, DMSO) δ 12.09 (s, 1H, 5-OH), the 9.08 (- OH of s, 1H, 3 '), 8.41 (t, J=5.8Hz, 1H, NH), 7.27-
7.20 (m, 1H, Ar-H), 7.14 (dd, J=7.4,1.4Hz, 1H, Ar-H), 6.93 (ddd, J=22.1,14.0,7.3Hz, 3H,
Ar-H, 2 '-H), 6.73 (dt, J=15.6,4.4Hz, 1H, C=OC=CH), 6.25 (d, J=15.6Hz, 1H, C=OCH=
), C 6.14 (d, J=2.3Hz, 1H, 8-H), 6.11 (d, J=2.3Hz, 1H, 6-H), 5.49 (dd, J=12.5,2.9Hz, 1H,
2-H), 4.83 (d, J=2.8Hz, 2H, C=CCH2), O 4.29 (d, J=5.8Hz, 2H, Ar-CH2N),3.79(s,3H,OCH3),
3.78(s,3H,OCH3), 3.26 (dd, J=17.2,12.6Hz, 1H, 3-H), 2.75 (dd, J=17.2,3.1Hz, 1H, 3-H)
.TOF-HRMS:m/z[M+H]+calcd for C28H28NO8:506.1809；found:506.1816.
Compound 3i chemical formula is as follows：
Embodiment 12：Compound 3j synthesis
Method, except that replacing benzyl ammonia with 3- methoxybenzyl ammonia, obtains white solid 3j with embodiment two.1H NMR
(400MHz, DMSO) δ 12.09 (s, 1H, 5-OH), the 9.08 (- OH of s, 1H, 3 '), 8.58 (t, J=5.9Hz, 1H, NH), 7.26-
7.20 (m, 1H, Ar-H), 6.96-6.92 (m, 2H, 2 '-H, 4 '-H), the 6.88 (- H of dd, J=8.4,2.0Hz, 1H, 5 '), 6.84-
6.79 (m, 3H, Ar-H), 6.74 (dt, J=15.6,4.4Hz, 1H, C=OC=CH), 6.21 (d, J=15.6Hz, 1H, C=
), OCH=C 6.14 (d, J=2.3Hz, 1H, 8-H), 6.11 (d, J=2.3Hz, 1H, 6-H), 5.49 (dd, J=12.5,
3.0Hz, 1H, 2-H), 4.84 (dd, J=4.2,1.5Hz, 2H, C=CCH2), O 4.30 (d, J=5.9Hz, 2H, Ar-CH2N),
3.78(s,3H,OCH3),3.72(s,3H,OCH3), 3.26 (dd, J=17.2,12.5Hz, 1H, 3-H), 2.75 (dd, J=
17.2,3.1Hz,1H,3-H).TOF-HRMS:m/z[M+H]+calcd for C28H28NO8:506.1809；found:
506.1816
Compound 3j chemical formula is as follows：
Embodiment 13：Compound 3k synthesis
Method is with embodiment two, except that replacing benzyl ammonia with phenyl ethylamine, obtains white solid 3k.1H NMR(400MHz,
CDCl3) δ 11.99 (s, 1H, 5-OH), 7.31 (dd, J=10.1,4.5Hz, 2H, Ar-H), 7.22 (ddd, J=16.0,6.8,
4.1Hz, 3H, Ar-H), the 7.03 (- H of d, J=2.0Hz, 1H, 2 '), 6.95-6.90 (m, 2H, 5 '-H, C=OC=CH), 6.88
(- the H of d, J=8.3Hz, 1H, 4 '), 6.02 (ddd, J=11.8,4.1,2.1Hz, 3H, 8-H, 6-H, C=OCH=C), 5.57 (t,
J=5.3Hz, 1H, NH), 5.32 (dd, J=12.8,3.0Hz, 1H, 2-H), 4.68 (dd, J=3.9,1.9Hz, 2H, C=
CCH2O),3.92(s,3H,OCH3), 3.61 (dd, J=12.9,6.8Hz, 2H, NCH2), 3.07 (dd, J=17.2,12.9Hz,
1H, 3-H), 2.85 (t, J=6.9Hz, 2H, Ar-CH2), 2.79 (dd, J=17.2,3.1Hz, 1H, 3-H) .TOF-HRMS:m/z
[M+H]+calcd for C28H28NO7:490.1860；found:490.1865
Compound 3k chemical formula is as follows：
Embodiment 14：Compound 3l synthesis
Method, except that with benzyl ammonia is replaced to methoxyphenethylamine, obtains white solid 3l with embodiment two.1H NMR
(400MHz,CDCl3) δ 11.99 (s, 1H, 5-OH), 7.13-7.08 (m, 2H, Ar-H), 7.03 (d, J=2.0Hz, 1H, 2 '-
), OH 6.95-6.82 (m, 5H, Ar-H, 4 '-H, 5 '-H, C=OC=CH), 6.06-5.98 (m, 3H, 6-H, 8-H, C=OCH=
), C 5.53 (t, J=5.6Hz, 1H, NH), 5.33 (dd, J=12.8,3.0Hz, 1H, 2H), 4.68 (dd, J=4.0,2.0Hz,
2H ,=CCH2O),3.92(s,3H,OCH3),3.79(s,3H,OCH3), 3.57 (q, J=6.8Hz, 2H, NCH2),3.07(dd,J
=17.2,12.9Hz, 1H, 3-H), 2.83-2.75 (m, 3H, Ar-CH2,3-H).TOF-HRMS:m/z[M+H]+calcd for
C29H30NO8:520.1966；found:520.1959.
Compound 3l chemical formula is as follows：
Embodiment 15：Compound 3m synthesis
Method, except that with benzyl ammonia is replaced to chlorophenethylamine, obtains white solid 3m with embodiment two.1H NMR
(400MHz, DMSO) δ 12.09 (s, 1H, 5-OH), the 9.08 (- OH of s, 1H, 3 '), 8.16 (t, J=5.6Hz, 1H, NH), 7.35-
7.30 (m, 2H, Ar-H), 7.25-7.20 (m, 2H, Ar-H), 6.96-6.92 (m, 2H, 2 '-H, 4 '-H), 6.88 (dd, J=
8.4,1.9Hz, 1H, 5 '-H), 6.68 (dt, J=15.6,4.4Hz, 1H, C=OC=CH), 6.11 (m, 3H, 8-H, 6-H, C=
), OCH=C 5.49 (dd, J=12.5,3.0Hz, 1H, 2-H), 4.82 (dd, J=4.1,1.4Hz, 2H, C=CCH2O),3.78
(s,3H,OCH3), 3.37 3.36 (dd, J=12.1,5.3Hz, 2H, NCH2), 3.26 (dd, J=17.2,12.5Hz, 1H, 3-
H),2.74(m,3H,3-H,Ar-CH2C).TOF-HRMS:m/z[M+H]+calcd for C18H27ClNO7:524.1471；
found:524.1481.
Compound 3m chemical formula is as follows：
Embodiment 16：Compound 3n synthesis
Method, except that with benzyl ammonia is replaced to Bretylium Tosylate, obtains white solid 3n with embodiment two.1H NMR
(400MHz, DMSO) δ 12.09 (s, 1H, 5-OH), the 9.08 (- OH of s, 1H, 3 '), 8.16 (t, J=5.6Hz, 1H, NH), 7.48-
7.43 (m, 2H, Ar-H), 7.16 (m, 2H, Ar-H), 6.96-6.91 (m, 2H, 2 '-H, 4 '-H), 6.88 (dd, J=8.4,
- the H of 2.0Hz, 1H, 5 '), 6.68 (dt, J=15.6,4.4Hz, 1H, C=OC=CH), 6.15-6.05 (m, 3H, 8-H, 6-H, C=
), OCHC=C 5.49 (dd, J=12.5,3.0Hz, 1H, 2-H), 4.81 (dd, J=4.1,1.4Hz, 2H, C=CCH2O),3.78
(s,3H,OCH3), 3.36 (dd, J=12.2,5.3Hz, 2H, NCH2), 3.26 (dd, J=17.2,12.5Hz, 1H, 3-H), 2.74
(dd, J=17.2,3.0Hz, 1H, 3-H), 2.70 (t, J=7.1Hz, 1H, Ar-CH2).TOF-HRMS:m/z[M+Na]+calcd
for C28H26BrNNaO7:590.0785；found:590.0799.
Compound 3n chemical formula is as follows：
Embodiment 17：Compound 3o synthesis
Method, except that with benzyl ammonia is replaced to fluorophenethylamine, obtains white solid 3o with embodiment two.1H NMR
(400MHz, DMSO) δ 12.09 (s, 1H, 5-OH), the 9.09 (- OH of s, 1H, 3 '), 8.16 (t, J=5.6Hz, 1H, NH), 7.26-
7.19 (m, 2H, Ar-H), 7.13-7.05 (m, 2H, Ar-H), 6.97-6.91 (m, 2H, 2 '-H, 4 '-H), 6.89 (dd, J=
8.4,1.9Hz, 1H, 5 '-H), 6.68 (dt, J=15.6,4.3Hz, 1H, C=OC=CH), 6.15-6.08 (m, 3H, C=OCH
=C, 6-H, 8-H), 5.49 (dd, J=12.5,3.0Hz, 1H, 2-H), 4.86-4.77 (dd, J=4.3,1.0Hz, 2H, C=
CCH2O),3.78(s,3H,OCH3), 3.34 (dd, J=7.4,5.7Hz, 2H, NCH2), 3.26 (dd, J=17.2,12.6Hz,
1H,3-H),2.74(m,3H,3-H,Ar-CH2C).TOF-HRMS:m/z[M+H]+calcd for C28H27FNO7:508.1766；
found:508.1767.
Compound 3o chemical formula is as follows：
Embodiment 18：Compound 3p synthesis
Method is with embodiment two, except that replacing benzyl ammonia with adjacent chlorophenethylamine, obtains white solid 3p.1H NMR
(400MHz, DMSO) δ 12.09 (s, 1H, 5-OH), the 9.09 (- OH of s, 1H, 3 '), 8.23 (t, J=5.7Hz, 1H, NH), 7.41
(dd, J=7.3,1.8Hz, 1H, Ar-H), 7.26 (m, 3H, Ar-H), 6.97-6.91 (m, 2H, 2 '-H, 4 '-H), 6.89 (dd, J
=8.4,1.9Hz, 1H, 5 '-H), 6.69 (dt, J=15.6,4.4Hz, 1H, C=OC=CH), 6.16-6.07 (m, 3H, C=
OCH=C, 6-H, 8-H), 5.49 (dd, J=12.5,3.0Hz, 1H, 2-H), 4.85-4.79 (m, 2H, C=CCH2O),3.78
(s,3H,OCH3), 3.37 (dd, J=13.2,7.0Hz, 2H, NCH2), 3.26 (dd, J=17.2,12.6Hz, 1H, 3-H), 2.86
(t, J=7.2Hz, 2H, Ar-CH2), CN 2.75 (dd, J=17.1,3.1Hz, 1H, 3-H) .TOF-HRMS:m/z[M+H]+calcd
for C28H27ClNO7:524.1471；found:524.1466.
Compound 3p chemical formula is as follows：
Embodiment 19：Compound 3q synthesis
Method is with embodiment two, except that replacing benzyl ammonia with adjacent fluorophenethylamine, obtains white solid 3q.1H NMR
(400MHz,CDCl3)δ11.99(s,1H,5-OH),7.25–7.16(m,2H,Ar-H),7.11–6.99(m,3H,Ar-H,2’-
), H 6.96-6.86 (m, 3H, C=OC=CH, 4 '-H, 5 '-H), 6.04 (m, 3H, C=OCH=C, 6-H, 8-H), 5.62 (t, J
=5.1Hz, 1H, NH), 5.33 (dd, J=12.8,2.9Hz, 1H, 2-H), 4.68 (d, J=1.0Hz, 2H, C=CCH2O),
3.92(s,3H,OCH3), 3.60 (dd, J=12.1,6.3Hz, 2H, NCH2), 3.07 (dd, J=17.2,12.9Hz, 1H, 3-H),
2.91 (t, J=6.7Hz, 2H, Ar-CH2), CN 2.79 (dd, J=17.2,3.0Hz, 1H, 3-H) .TOF-HRMS:m/z[M+H]+
calcd for C28H27FNO7:508.1766；found:508.1773.
Compound 3q chemical formula is as follows：
Embodiment 20：Compound 3r synthesis
Method is with embodiment two, except that chlorophenethylamine replaces benzyl ammonia between, obtains white solid 3r.1H NMR
(400MHz,CDCl3) δ 11.99 (s, 1H, 5-OH), 7.25-7.15 (m, 3H, Ar-H), 7.08 (dd, J=6.7,1.6Hz, 1H,
), Ar-H the 7.03 (- H of d, J=1.9Hz, 1H, 2 '), 6.97-6.86 (m, 3H, C=OC=CH, 4 '-H, 5 '-H), 6.11-5.99
(m, 3H, C=OCH=C, 6-H, 8-H), 5.61 (t, J=4.9Hz, 1H, NH), 5.32 (dd, J=12.8,3.0Hz, 1H, 2-
), H 4.74-4.66 (m, 2H, C=CCH2O),3.92(s,3H,OCH3), 3.59 (q, J=6.7Hz, 2H, NCH2),3.07(dd,J
=17.2,12.9Hz, 1H, 3-H), 2.81 (dt, J=17.2,5.0Hz, 3H, Ar-CH2CN,3-H).TOF-HRMS:m/z[M+
H]+calcd for C28H27ClNO7:524.1471；found:524.1471.
Compound 3r chemical formula is as follows：
Embodiment 21：Compound 3s synthesis
Method is with embodiment two, except that replacing benzyl ammonia with pyrrolidines, obtains white solid 3s.1H NMR(400MHz,
CDCl3) δ 11.99 (s, 1H, 5-OH), the 7.04 (- H of d, J=2.0Hz, 1H, 2 '), 6.99 (dt, J=15.2,4.1Hz, 1H, C=
), OC=CH the 6.92 (- H of dd, J=8.4,2.0Hz, 1H, 5 '), the 6.88 (- H of d, J=8.3Hz, 1H, 4 '), 6.43 (dt, J=
15.3,1.7Hz, 1H, C=OCH=C), 6.08 (d, J=2.3Hz, 1H, 8-H), 6.06 (d, J=2.3Hz, 1H, 6-H), 5.33
(dd, J=12.8,3.0Hz, 1H, 2-H), 4.71 (dd, J=4.0,1.8Hz, 2H, C=CCH2),3.92(s,3H,OCH3),
3.54 (t, J=6.4Hz, 4H, NCH2), 3.08 (dd, J=17.2,12.8Hz, 1H, 3-H), 2.80 (dd, J=17.2,
3.1Hz,1H,3-H),1.93(m,4H,NCCH2).TOF-HRMS:m/z[M+H]+calcd for C24H26NO7:440.1704；
found:440.1710.
Compound 3s chemical formula is as follows：
Embodiment 22：Compound 3t synthesis
Method is with embodiment two, except that replacing benzyl ammonia with chaff amine, obtains white solid 3t.1H NMR(400MHz,
CDCl3) δ 11.99 (s, 1H, 5-OH), 7.35 (dd, J=1.7,0.6Hz, 1H, Fu-H), 7.03 (d, J=2.0Hz, 1H, 2 '-
), H 6.96 (dt, J=15.4,4.4Hz, 1H, C=OC=CH), the 6.92 (- H of dd, J=8.4,2.1Hz, 1H, 5 '), 6.88 (d, J
=8.3Hz, 1H, 4 '-H), 6.32 (dd, J=3.2,1.9Hz, 1H, Fu-H), 6.25 (d, J=3.2Hz, 1H, Fu-H), 6.09
(dt, J=15.4,1.9Hz, 1H, C=OCH=C), 6.05 (d, J=2.3Hz, 1H, 8-H), 6.03 (d, J=2.3Hz, 1H, 6-
), H 5.87 (t, J=4.8Hz, 1H, NH), 5.33 (dd, J=12.8,3.0Hz, 1H, 2-H), 4.70 (dd, J=3.9,2.0Hz,
2H,NCH2), 4.52 (d, J=5.5Hz, 2H, C=CCH2O),3.92(s,3H,OCH3), 3.07 (dd, J=17.2,12.9Hz,
1H, 3-H), 2.79 (dd, J=17.2,3.1Hz, 1H, 3-H) .TOF-HRMS:m/z[M+H]+calcd for C25H24NO8:
466.1496；found:466.1489.
Compound 3t chemical formula is as follows：
Embodiment 23：Compound 3u synthesis
Method is with embodiment two, except that replacing benzyl ammonia with n-propylamine, obtains white solid 3u.1H NMR(400MHz,
CDCl3) δ 11.99 (s, 1H, 5-OH), the 7.04 (- H of d, J=2.0Hz, 1H, 2 '), 6.96-6.86 (m, 3H, 4 '-H, 5 '-H, C=
), OC=CH 6.12-6.03 (m, 3H, C=OCH=C, 6-H, 8-H), 5.59-5.51 (t, J=3.6Hz, 1H, NH), 5.33
(dd, J=12.8,3.0Hz, 1H, 2-H), 4.70 (dd, J=4.0,2.0Hz, 2H, C=CCH2O),3.92(s,3H,OCH3),
3.30 (dd, J=13.7,6.5Hz, 2H, NCH2), 3.08 (dd, J=17.2,12.9Hz, 1H, 3-H), 2.80 (dd, J=
17.2,3.1Hz,1H,3-H),1.54(m,2H,NCCH2), 0.94 (t, J=7.4Hz, 3H, CH3).TOF-HRMS:m/z[M+Na
]+calcd for C23H25NNaO7:450.1523；found:450.1529.
Compound 3u chemical formula is as follows：
Embodiment 24：Compound 3v synthesis
Method is with embodiment two, except that replacing benzyl ammonia with n-butylamine, obtains white solid 3v.1H NMR(400MHz,
CDCl3) δ 11.99 (s, 1H, 5-OH), the 7.04 (- H of d, J=2.0Hz, 1H, 2 '), 6.96-6.86 (m, 3H, C=OC=CH, 4 '-
H, 5 '-H), 6.11-6.02 (m, 3H, C=OCH=C, 6-H, 8-H), 5.56 (t, J=4.8Hz, 1H, NH), 5.33 (dd, J=
12.8,3.0Hz, 1H, 2-H), 4.69 (dd, J=4.0,2.0Hz, 2H ,=CCH2O),3.92(s,3H,OCH3),3.34(dd,J
=13.0,7.0Hz, 2H, NCH2), 3.08 (dd, J=17.2,12.9Hz, 1H, 3-H), 2.79 (dd, J=17.2,3.1Hz,
1H,3-H),1.57–1.46(m,2H,CH2),1.44–1.29(m,2H,CH2), 0.93 (t, J=7.3Hz, 3H, CH3).TOF-
HRMS:m/z[M+H]+calcd for C24H28NO7:442.1860；found:442.1869.
Compound 3v chemical formula is as follows：
Embodiment 25：Compound 3w synthesis
Method is with embodiment two, except that replacing benzyl ammonia with isobutyl amine, obtains white solid 3w.1H NMR(400MHz,
CDCl3) δ 11.99 (s, 1H, 5-OH), the 7.04 (- H of d, J=2.0Hz, 1H, 2 '), 6.96-6.90 (m, 2H, 5 '-H, C=OC=
), CH the 6.88 (- H of d, J=8.3Hz, 1H, 4 '), 6.10 (dt, J=15.3,2.0Hz, 1H, C=OCH=C), 6.06 (d, J=
2.3Hz, 1H, 8-H), 6.04 (d, J=2.3Hz, 1H, 6-H), 5.62 (t, J=5.5Hz, 1H, NH), 5.33 (dd, J=12.8,
3.0Hz, 1H, 2-H), 4.69 (dd, J=4.0,2.0Hz, 2H, C=OC=CCH2O),3.92(s,3H,OCH3), 3.17 (t, J=
6.5Hz,2H,NCH2), 3.08 (dd, J=17.2,12.9Hz, 1H, 3-H), 2.79 (dd, J=17.2,3.1Hz, 1H, 3-H),
1.81 (dp, J=13.5,6.7Hz, 1H, NCCH), 0.94 (s, 3H, CH3),0.92(s,3H,CH3).TOF-HRMS:m/z[M+H
]+calcd for C24H28NO7:442.1860；found:442.1863.
Compound 3w chemical formula is as follows：
Embodiment 26：Compound 3x synthesis
Method is with embodiment two, except that replacing benzyl ammonia with N methyl piperazine, obtains white solid 3x.1H NMR
(400MHz,DMSO)δ12.08(s,1H,5-OH),9.08(s,1H,3’-OH),6.95–6.92(m,2H,2’-H,4’-H),
The 6.88 (- H of dd, J=8.4,2.0Hz, 1H, 5 '), 6.76 (d, J=15.3Hz, 1H, C=OC=CH), 6.69 (dt, J=15.2,
4.5Hz, 1H, C=OCH=C), 6.17 (d, J=2.3Hz, 1H, 8-H), 6.14 (d, J=2.3Hz, 1H, 6-H), 5.49 (dd, J
=12.4,3.0Hz, 1H, 2-H), 4.81 (d, J=3.9Hz, 2H, C=CCH2O),3.78(s,3H,OCH3),3.51(m,4H,C
=ONCH2), 3.26 (dd, J=17.2,12.5Hz, 1H, 3-H), 2.75 (dd, J=17.2,3.1Hz, 1H, 3-H), 2.27 (s,
4H,NCH2),2.17(s,3H,NCH3).TOF-HRMS:m/z[M+H]+calcd for C25H29N2O7:469.1969；found:
469.1971.
Compound 3x chemical formula is as follows：
Embodiment 27：Compound 3y synthesis
Method is with embodiment two, except that replacing benzyl ammonia with NEP, obtains white solid 3y.1H NMR
(400MHz,DMSO)δ12.08(s,1H,5-OH),9.08(s,1H,3’-OH),6.95–6.92(m,2H,2’-H,4’-H),
The 6.88 (- H of dd, J=8.4,2.0Hz, 1H, 5 '), 6.76 (d, J=15.3Hz, 1H, C=OC=CH), 6.69 (dt, J=15.2,
4.4Hz, 1H, C=OCH=C), 6.17 (d, J=2.3Hz, 1H, 8-H), 6.14 (d, J=2.3Hz, 1H, 6-H), 5.49 (dd, J
=12.4,3.0Hz, 1H, 2-H), 4.81 (d, J=4.0Hz, 2H, C=CCH2O),3.78(s,3H,OCH3),3.51(m,4H,C
=NCH2), 3.26 (dd, J=17.2,12.5Hz, 1H, 3-H), 2.76 (dd, J=17.2,3.1Hz, 1H, 3-H), 2.37-
2.26(m,6H,N(CH2)3), 0.99 (t, J=7.2Hz, 3H, NCCH3).TOF-HRMS:m/z[M+H]+calcd for
C26H30N2O7:483.2126；found:483.2123.
Compound 3y chemical formula is as follows：
Apply example 28：Compound 3z synthesis
Method is with embodiment two, except that replacing benzyl ammonia with morpholine, obtains white solid 3z.1H NMR(400MHz,
CDCl3) δ 11.99 (s, 1H, 5-OH), the 7.04 (- H of d, J=2.0Hz, 1H, 2 '), 7.00-6.90 (m, 2H, 5 '-H, C=OC=
), CH the 6.88 (- H of d, J=8.3Hz, 1H, 4 '), 6.55 (d, J=15.2Hz, 1H, C=OCH=C), 6.08 (d, J=2.3Hz,
1H, 8-H), 6.06 (d, J=2.3Hz, 1H, 6-H), 5.34 (dd, J=12.8,3.0Hz, 1H, 2-H), 4.71 (dd, J=3.7,
1.7Hz, 2H, C=CCH2O),3.92(s,3H,OCH3),3.73–3.48(m,8H,NCH2CH2N), 3.08 (dd, J=17.2,
12.8Hz, 1H, 3-H), 2.80 (dd, J=17.2,3.1Hz, 1H, 3-H) .TOF-HRMS:m/z[M+H]+calcd for
C24H26NO8:456.1653；found:456.1654.
Compound 3z chemical formula is as follows：
Apply example 29：Compound 4a synthesis
Method is with embodiment two, except that replacing benzyl ammonia with diethylamine, obtains white solid 3z.1H NMR(400MHz,
CDCl3) δ 11.99 (s, 1H, 5-OH), the 7.04 (- H of d, J=2.0Hz, 1H, 2 '), 6.96 (dt, J=15.0,3.8Hz, 1H, C=
), OC=CH the 6.91 (- H of dd, J=2.0,8.3Hz, 1H, 5 '), the 6.88 (- H of d, J=8.3Hz, 1H, 4 '), 6.52 (dt, J=
15.2,1.8Hz, 1H, C=OCH=C), 6.08 (d, J=2.3Hz, 1H, 8-H), 6.07 (d, J=2.3Hz, 1H, 6-H), 5.33
(dd, J=12.8,3.0Hz, 1H, 2-H), 4.71 (dd, J=4.2,1.9Hz, 2H, C=CCH2O),3.92(s,3H,OCH3),
3.40 (dq, J=31.1,6.7Hz, 4H, NCH2), 3.08 (dd, J=17.2,12.8Hz, 1H, 3-H), 2.80 (dd, J=
17.2,3.1Hz, 1H, 3-H), 1.17 (q, J=6.8Hz, 6H, CH3).TOF-HRMS:m/z[M+H]+calcd for
C24H28NO7:442.1860；found:422.1865.
Compound 4a chemical formula is as follows：
Anti-inflammatory activity screening experiment step and result
1) preparation of compound solution：Test compound is made into 100 μM of concentration (solvents：DMSO), -20 DEG C of low temperature are protected
Deposit, during use with required cell culture medium needed for concentration.
2) culture of cell
This experiment RAW264.7 macrophages used are adherent growth cell line, using the DMEM containing 10% hyclone
Nutrient solution is cultivated.Culture environment is 37 DEG C, 5%CO2Incubator, a nutrient solution is changed daily, is taken in logarithmic growth
The cell of phase is tested.
3) NO discharges the measure of content
Take the logarithm the RAW264.7 cells of proliferation period, 70,000 cells are inoculated with every hole and cultivated in 24 orifice plate kinds, incubator
One day, after then continuing culture 2 hours per the medicine (5,10,20,30,40 μM) of Kong Zhongjia various concentrations, 1 μ g/ are added per hole
ML LPS is stimulated 24 hours, and blank control adds the culture medium of equivalent.The supernatant in each hole is drawn, centrifuges 4 DEG C, 12000rpm/
Min rotating speed centrifuges 5 minutes, collects supernatant.Nitric oxide production measure is reacted with Griess Reagent.Add Griess
Each 50 μ L of Reagent I and Griess Reagent II.Reaction 10 minutes, absorbance is determined with ELIASA 540nm.
Experimental result is the average value of independent experiment three times, and we are represented with nitric oxide production inhibiting rate.
Discussion of results：Synthesized compound has a good NO inhibitions, compound 2,3a-d, 3h, 3j-k, 3o,
3q-t, 3x-y, 4a reach more than 60% to NO inhibiting rates.Prove release of these medicines to a certain extent to inflammatory factor NO
There is certain inhibition.
4) suppression of IL-6 and TNF-α secretion influences
Equally take the logarithm the macrophage of proliferation period.With every hole 7 × 104The cell density inoculating cell in individual/hole is in 24 holes
In plate.Add 2 hours (drug concentrations of various concentrations medicine culture：5,10,20,30,40 μM), without any processing of blank control
Add the culture medium of equivalent, add the stimulation of 1ug/mL LPS solution, continue culture 24 hours.Draw each hole supernatant, centrifuge 4
DEG C, 10000rpm/min rotating speed centrifuges 5 minutes, takes supernatant.Illustrate to operate according to ELISA kit.Then 450nm wavelength
Place determines each hole value.
Experimental result is independent 3 average value tested.
As a result prove that compound 3x and 3h most can significantly suppress the release of inflammatory factor IL-6 and TNF-α.These are changed
3x and 3h most possibly develop into anti-inflammatory drug in compound.
Claims (6)
1. the hesperetin analog derivative of a kind of amide groups substitution, it is characterised in that its structural formula is：
Wherein R1 represents diethylin, n-propylamine base, n-butylamine-based, isobutyl amine, pyrrolidinyl, sugared amino, N methyl piperazine
Base, NEP base, morpholine base, benzene ethylamino, adjacent chlorobenzene ethylamino, adjacent fluorobenzene ethylamino, a chlorobenzene ethylamino, to bromine
Benzene ethylamino, to chlorobenzene ethylamino, to fluorophenethyl amido, to methoxybenzene ethylamino, benzyl amino, O-methoxy benzamido group,
Methoxybenzyl amido, 4-Methoxybenzylamine base, adjacent fluorine benzyl amino, adjacent benzyl chloride amino, to benzyl chloride amino, to fluorine benzyl amino, to bromine
Benzyl amino, benzylamino, in one kind.
A kind of 2. preparation method of the hesperetin analog derivative of amide groups substitution as claimed in claim 1, it is characterised in that bag
Include following steps：
(1) by hesperetinStirred with the 3-5 times of crotonic ethyl bromide measured under weak base effect
After obtain product
(2) after step (1) products therefrom being hydrolyzed into reaction, then mix with various amine, acid amides substitution reaction obtains end-product
The hesperetin analog derivative of amide groups substitutionR1 is diethylin, positive third
Amido, n-butylamine-based, isobutyl amine, pyrrolidinyl, sugared amino, N methyl piperazine base, NEP base, morpholine base, benzene
Ethylamino, adjacent chlorobenzene ethylamino, adjacent fluorobenzene ethylamino, a chlorobenzene ethylamino, to bromobenzene ethylamino, to chlorobenzene ethylamino, to fluorine
Phenyl ethylamine base, to methoxybenzene ethylamino, benzyl amino, O-methoxy benzamido group, meta-methoxy benzamido group, 4-Methoxybenzylamine
Base, adjacent fluorine benzyl amino, adjacent benzyl chloride amino, to benzyl chloride amino, to fluorine benzyl amino, to bromobenzylamino, in benzylamino
It is a kind of.
A kind of 3. preparation method of the hesperetin analog derivative of amide groups substitution as claimed in claim 2, it is characterised in that：Step
Suddenly weak base is K in (1)2CO3, mixing time is 1 hour, reaction dissolvent DMF.
A kind of 4. preparation method of the hesperetin analog derivative of amide groups substitution as claimed in claim 2, it is characterised in that step
Suddenly hydrolysis reaction condition is NaOH catalysis in (2), and solvent is water and methanol, condition of ice bath；Acid amides substitution reaction is in HOBT and EDC
Under the catalysis of hydrochloride, solvent is chloroform.
5. a kind of application of the hesperetin analog derivative of amide groups substitution as claimed in claim 1, it is characterised in that as system
Application in the medicine of standby anti-inflammatory.
6. the application of the hesperetin analog derivative of amide groups substitution as claimed in claim 5, it is characterised in that described medicine
For one kind in injection, tablet, pill, capsule, suspending agent or emulsion.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110372657A (en) * | 2019-08-15 | 2019-10-25 | 安徽医科大学 | A kind of hesperetin analog derivative and its preparation method and application that 7-O- amide groups replaces |
| CN113773295A (en) * | 2021-09-26 | 2021-12-10 | 广东省科学院动物研究所 | Synthesis method of mono-substituted dihydrochromone and application of mono-substituted dihydrochromone in treating lung inflammation such as COPD (chronic obstructive pulmonary disease) |
| WO2023045302A1 (en) * | 2021-09-26 | 2023-03-30 | 广东省科学院动物研究所 | Method for synthesizing disubstituted benzodihydropyrone compound and use thereof in treatment of pulmonary inflammations such as copd |
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|---|---|---|---|---|
| US4348333A (en) * | 1981-10-09 | 1982-09-07 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | β-Ketocarboxyl and phosphonate dihydro-chalcone sweeteners |
| CN106905280A (en) * | 2017-02-24 | 2017-06-30 | 安徽医科大学 | Hesperetin analog derivative of a kind of amide groups substitution and preparation method thereof and as the application in the medicine of anti-alzheimer's disease |
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2017
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4348333A (en) * | 1981-10-09 | 1982-09-07 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | β-Ketocarboxyl and phosphonate dihydro-chalcone sweeteners |
| CN106905280A (en) * | 2017-02-24 | 2017-06-30 | 安徽医科大学 | Hesperetin analog derivative of a kind of amide groups substitution and preparation method thereof and as the application in the medicine of anti-alzheimer's disease |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110372657A (en) * | 2019-08-15 | 2019-10-25 | 安徽医科大学 | A kind of hesperetin analog derivative and its preparation method and application that 7-O- amide groups replaces |
| CN113773295A (en) * | 2021-09-26 | 2021-12-10 | 广东省科学院动物研究所 | Synthesis method of mono-substituted dihydrochromone and application of mono-substituted dihydrochromone in treating lung inflammation such as COPD (chronic obstructive pulmonary disease) |
| WO2023045302A1 (en) * | 2021-09-26 | 2023-03-30 | 广东省科学院动物研究所 | Method for synthesizing disubstituted benzodihydropyrone compound and use thereof in treatment of pulmonary inflammations such as copd |
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